Tumor suppressor gene networks act to limit the growth of malignant tumors and can influence the response of tumors to conventional and targeted anticancer agents. Project 6 (Tumor Suppression) is interested in uncovering innate tumor suppressive mechanisms involved in coupling proliferation to apoptotic cell death, and determining how mutations that disable these safeguards influence tumorigenesis. We previously used the adenoviral E1A protein to demonstrate how oncogene-induced apoptosis can be activated and executed through p53-dependent and independent mechanisms. More recently, we used mouse models to establish the importance of oncogene-induced apoptosis in tumor suppression, and identified key apoptotic regulators whose activation or disruption cooperates with Myc during tumorigenesis. In addition, our project has developed some powerful tools to probe tumor suppressor gene networks in vivo, including chimeric mouse models of lymphoma and hepatocellular carcinoma, and in vivo RNAi technology to suppress gene function in a stable or reversible manner. Moving forward, we will continue to explore the underlying mechanisms of oncogene-induced apoptosis in vivo, now taking a comparative approach that examines Myc-induced tumorigenesis in a lymphoid and epithelial cancer, and exploiting rapid methods for identifying and characterizing crucial genes in tumor suppressor networks in vivo. First, we will characterize p53-dependent and independent components of oncogene-induced apoptotic programs and determine how they impact tumorigenesis in distinct tumor types. Second, we will explore how deregulated survival signaling through the PIS kinase pathway or via altered translational control evades oncogene-induced apoptosis and promotes tumorigenesis. Third, we will use conditional RNA interference technology to determine the role of p53 and p53 mutations in tumor maintenance. Finally, we will conduct high throughput genetic screens to identify components of tumor suppressor networks whose disruption promotes tumorigenesis in vivo. By understanding how oncogenes engage the apoptotic network and how tumor cells escape this process, we hope to produce new insights into the workings of innate tumor suppressor mechanisms and identify new drug targets and therapeutic approaches.